Synthesis of novel 2,3-dihydro-3-hydroperoxy-2-aryl-4,5-diphenylisothiazole 1,1-dioxides and their epoxidation ability

Article abstract of DOI:10.1002/jhet.350

(Chemical Equation Presented) The novel hydroperoxy sultams, 2,3-dihydro-3-hydroperoxy-2-aryl-4,5-diphenylisothiazole 1,1-dioxides, were synthesized by the oxidation of the 2-aryl-4,5-diphenyl substituted isothiazolium salts with H₂O₂

Full text of DOI:10.1002/jhet.350

846
Synthesis of Novel 2,3-Dihydro-3-hydroperoxy-2-aryl-4,5-
diphenylisothiazole 1,1-Dioxides and Their Epoxidation Ability
Vol 47
Oksana Makota,a* Janine Wolf,b Yuriy Trach,a and Barbel Schulzeb
aInstitute of Chemistry and Chemical Technologies, Lviv Polytechnic National University,
U-79013 Lviv, Ukraine
bInstitute of Organic Chemistry, Leipzig University, Johannisallee 29, D-04103 Leipzig, Germany
*E-mail: makotaoksana@yahoo.com
Received September 11, 2009
DOI 10.1002/jhet.350
Published online 4 June 2010 in Wiley InterScience (www.interscience.wiley.com).
The novel hydroperoxy sultams, 2,3-dihydro-3-hydroperoxy-2-aryl-4,5-diphenylisothiazole 1,1-diox-
ides, were synthesized by the oxidation of the 2-aryl-4,5-diphenyl substituted isothiazolium salts with
H2O2. These hydroperoxy sultams were investigated as epoxidation agents in the epoxidation reaction
of cis-cyclooctene catalyzed by MoB. 2-(2-Chlorophenyl)-2,3-dihydro-3-hydroperoxy-4,5-diphenyliso-
thiazole 1,1-dioxide was found to have the highest epoxidation ability.
J. Heterocyclic Chem., 47, 846 (2010).
INTRODUCTION
[20,21]. The oxidation of the 2-aryl-4,5-diphenyl substi-
tuted isothiazolium salts in glacial acetic acid with 30%
H2O2 at r.t. gave stable 3-hydroperoxysultams (2) in
good yields: 2-(2-chlorophenyl)-2,3-dihydro-3-hydroper-
oxy-4,5-diphenylisothiazole 1,1-dioxide (2a) (70%), 2-
(2,6-dichlorophenyl)-2,3-dihydro-3-hydroperoxy-4,5-diphe-
nylisothiazole 1,1-dioxide (2b) (70%) and 2-(2,6-dichloro-
4-nitrophenyl)-2,3-dihydro-3-hydroperoxy-4,5-diphenyliso-
thiazole 1,1-dioxide (2c) (72%) after 72, 72 and 96 h
stirring, respectively.
The cyclic sulfonamides (sultams) have been shown
to be highly useful heterocycles for medicinal chemistry
[1,2] as well as for chemical methodology [3,4]. They
show biological activities such as antibacterial [5,6],
anticonvulsant [7,8], sedative-hypnotic [9], and peptido-
mimetic [10,11]. Sultams have found application as chi-
ral auxiliaries in several asymmetric processes such as
Diels-Alder reactions [12,13], alkylation [14], and di-
hydroxylation [15] and are used in enantioselective ca-
talysis [16]. Hydroperoxy sultams can also serve as oxi-
dants in oxidation of heteroatoms (N, S, P) [17,18] and
in epoxidation of double bonds [19].
The structures of the 3-hydroperoxysultams 2a, 2b,
and 2c were established by IR and NMR spectroscopy
and composition was confirmed by mass spectrometry
and elemental analysis.
We now report the synthesis of novel hydroperoxy
sultams, 2,3-dihydro-3-hydroperoxy-2-aryl-4,5-diphenyli-
sothiazole 1,1-dioxides, and studies of their epoxidation
ability in the epoxidation reaction of cis-cyclooctene
catalyzed by molybdenum boride MoB.
The IR spectra of compounds 2 show two absorption
bands at 1302–1316 and 1146–1160 cmꢀ1 for the SO2
groups which are characteristic for the antisymmetric
and symmetric vibrations of the 1,1-dioxides, respec-
tively. The two absorption bands for the NO2 group are
observed at 1335 and 1537 cmꢀ1 in the spectrum of
compound 2c.
In 1H NMR spectra of 3-hydroperoxysultams 2, the
typical absorption of the 3-H atom appears at 6.49–6.60
ppm. The 13C NMR signals for C-3 at 92.5–95.0 ppm
are characteristic for compounds 2.
RESULTS AND DISCUSSION
Our approach to hydroperoxy sultams started from
isothiazolium salts (1) (Scheme 1) which were prepared
for the first time by intramolecular cyclocondensation of
b-thiocyanatovinyl aldehydes and the suitably substi-
tuted anilines in the presence of perchloric acid in acetic
acid in moderate-to-good yields: 1a (61%), 1b (62%),
and 1c (51%) according to already reported synthesis
The 2 were investigated as epoxidation agents in the
epoxidation reaction of cyclooctene in the presence of
molybdenum boride. The kinetic curves of 2 consump-
tion and 1,2-epoxycyclooctane accumulation in the
C
V
2010 HeteroCorporation

July 2010
Synthesis of Novel 2,3-Dihydro-3-hydroperoxy-2-aryl-4,5-diphenylisothiazole
1,1-Dioxides and Their Epoxidation Ability
847
Scheme 1
Figure 2. The kinetic curves of the 1,2-epoxycyclooctane accumula-
tion in the catalytic epoxidation reaction of cyclooctene by 2.
containing only one ortho-chlorine atom and conversion
of this hydroperoxide was equal to 73% after 40 min of
reaction. In the case of 2b with two chlorine atoms in
ortho-position to bond of nitrogen with aromatic ring,
the hydroperoxide consumption was the lowest and hy-
droperoxide conversion was 41%. The value of hydro-
peroxide conversion for 2c which contains three sub-
stituents—two chlorine atoms and one NO2 group—is
47% so it is between 2a and 2b.
epoxidation process are presented in Figures 1 and 2,
respectively. It is evident that epoxidation ability of
investigated 2 is different and is defined by the nature
of the substituents on the aromatic ring connected at
nitrogen atom of hydroperoxide molecule.
The highest value of hydroperoxy sultam consumption
in the catalytic epoxidation process was observed for 2a
The epoxide is formed in the presence of all investi-
gated hydroperoxy sultams. This fact indicates on possi-
bility of their application as epoxidation agents in the
catalytic reaction with cyclooctene. The highest epoxida-
tion ability exhibits 2a, the selectivity of epoxide forma-
tion (calculated as ratio of formed epoxide quantity to
consumed hydroperoxide quantity) in its presence is
35%. The lowest epoxidation ability demonstrates 2c in
the case of which the selectivity of epoxide formation is
only 5%. 2b shows intermediate selectivity 19%.
From the obtained results, one can conclude that the
most effective oxidant in the catalytic epoxidation reac-
tion of cyclooctene is 2a, which molecule contains only
one substituent—chlorine atom in a-position to bond of
nitrogen with aromatic ring. Introduction of another one
chlorine atom and especially NO2 group leads to
decrease of the parameters of the epoxidation reaction.
It is probably caused by dominant influence of a steric
factor. The increase in quantity of substituents compli-
cates possibility of the simultaneous coordination of
hydroperoxy sultam and cyclooctene on catalyst and for-
mation of intermediate triple complex which is
Figure 1. The kinetic curves of the consumption of 2 in the catalytic
epoxidation reaction of cyclooctene.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

848
O. Makota, J. Wolf, Y. Trach, and B. Schulze
Vol 47
EXPERIMENTAL
Melting points were determined on Boetius micro-melting-
point apparatus and are corrected. IR spectra are expressed in
cmꢀ1 and were recorded on Genisis FTIR Unicam Analytical
System (ATI Mattson) using KBr pellets. 1H NMR spectra
were recorded on 200- (Varian Gemini-200) and 300-MHz
(Varian Gemini-300). Chemical shifts are reported in d (ppm)
relative to tetramethylsilane (TMS) as internal standard. 13C
NMR spectra were received on the named spectrometers. Elec-
tron impact mass spectra (EI-MS) were recorded on a Quadru-
pol-MS VG 12-250 at an ionizing voltage of 70 eV. Elemental
analysis was determined on Heraeus CHNO Rapid Analyzer.
Synthesis of 2,3-dihydro-3-hydroperoxy-2-aryl-4,5-diphe-
nylisothiazole 1,1-dioxides (2). H2O2 (0.7 mL, 30%) was
added to a stirred suspension of 1 (0.26 mmol) in AcOH (0.7
mL) at room temperature. After dissolution of salts 1, colorless
precipitates of 2 were obtained after 72–96 h and isolated. The
crude products were washed with water.
2-(2-Chlorophenyl)-2,3-dihydro-3-hydroperoxy-4,5-dipheny-
lisothiazole 1,1-dioxide (2a). Mp 197–201ꢁC; IR (KBr) 1157,
1
1302 (SO2) cmꢀ1; H NMR (200 MHz, acetone-d6) d 6.60 (s,
1H, 3–H), 7.37–7.96 (m, 14H, ArH), 11.38 (s, 1H, OOH); 13C
NMR (50 MHz, acetone-d6) d ¼ 92.5, 128.1, 128.9, 129.5,
129.9, 130.0, 130.4, 130.7, 130.9, 131.6, 131.7, 131.8, 135.0,
135.6, 139.1; EI-MS m/z 413.0 (Mþꢂ). Anal. Calcd. for
C21H16ClNO4S: C, 60.94; H, 3.90; N, 3.38; O, 15.46. Found:
C, 60.60; H, 4.01; N, 3.55; O, 15.80.
Figure 3. The kinetic curves of the consumption of 2 in the catalytic
decomposition reaction.
responsible for epoxide formation [22–24]. Accordingly,
the efficiency of the epoxidation reaction decreases.
Taking into account the significant contribution of
unproductive 2 consumption into overall process of the
cyclooctene epoxidation, it is reasonable to study the
decomposition process of investigated hydroperoxy sul-
tams catalyzed by MoB at the same reaction conditions
in the absence of cyclooctene in the reaction system.
Figure 3 shows the kinetic curves of 3-hydroperoxysul-
tams consumption in the process of catalytic decomposi-
tion. One can see that the decomposition process most
actively occurs in the case of 2c with hydroperoxide con-
version 63%. One may suggest that presence of NO2
group in a para-position to bond of nitrogen with aromatic
ring favors the proceeding of the catalytic decomposition
process. The values of conversions of 2b and 2a are
smaller and are equal to 52% and 43%, correspondingly.
Comparing the data of the decomposition process with
the data of the epoxidation process, it is possible to conclude
that the highest epoxidation ability in the epoxidation pro-
cess has 2a which is the least active in the decomposition
reaction. At the same time, the 2c, which is the most actively
consumed in the decomposition process, has the lowest
epoxidation ability in the reaction with cyclooctene.
2-(2,6-Dichlorophenyl)-2,3-dihydro-3-hydroperoxy-4,5-
diphenylisothiazole 1,1-dioxide (2b). Mp 124–127ꢁC; IR
1
(KBr) 1160, 1313 (SO2) cmꢀ1; H NMR (300 MHz, acetone-
d6) d 6.49 (s, 1H, 3–H), 7.25–7.64 (m, 13H, ArH), 11.23 (s,
1H, OOH); 13C NMR (50 MHz, acetone-d6) d 95.0, 130.1,
130.3, 130.6, 130.7, 130.9, 131.0, 131.1, 131.3, 131.5, 131.7,
132.4, 132.9, 138.2, 139.4, 140.8; EI-MS m/z 447.0 (Mþꢀ).
Anal. Calcd. for C21H15Cl2NO4S: C, 56.26; H, 3.37; N, 3.12;
O, 14.27. Found: C, 55.40; H, 3.56; N, 3.13; O, 14.00.
2-(2,6-Dichloro-4-nitrophenyl)-2,3-dihydro-3-hydroperoxy-
4,5-diphenylisothiazole 1,1-dioxide (2c). Mp 148–151ꢁC; IR
(KBr) 1146, 1316 (SO2), 1335, 1537 (NO2) cmꢀ1 1H NMR
;
(200 MHz, acetone-d6) d 6.58 (s, 1H, 3–H), 7.38–7.50 (m,
10H, ArH), 8.14 (s, 1H, ArH), 8.45 (s, 1H, ArH), 11.55 (s,
1H, OOH); 13C NMR (50 MHz, acetone-d6) d 94.8, 125.6,
125.7, 126.1, 128.2, 130.1, 130.2, 130.4, 130.5, 130.6, 130.8,
131.0, 131.2, 131.7, 131.9, 139.4; EI-MS m/z 474.0 (M-
H2O)þꢂ. Anal. Calcd. for C21H14Cl2N2O6S: C, 51.13; H, 2.86;
N, 5.68; O, 19.46. Found: C, 50.83; H, 2.89; N, 5.72; O,
19.20.
General experimental procedure for the catalytic epoxi-
dation of cyclooctene by 2. The epoxidation process was car-
ried out in a thermostated glass reactor fitted with a reflux con-
denser and a magnetic stirrer under an argon atmosphere at
temperature 23ꢁC. The reactor was loaded with 0.01 g of MoB
(Alfa Aesar) as a heterogeneous catalyst, 0.3 mL of cis-cyclo-
octene (Acros Organics), 3.5 mL chloroform as solvent, and
0.01 mol Lꢀ1 of 2. It is established that 2 does not decompose
in the absence of catalyst in the reaction system and 1,2-epox-
ycyclooctane is not formed under the reaction conditions. The
concentration of 2 was determined by iodometric titration [25].
The reaction mixtures were analyzed by using a Hewlett Pack-
ard HP 6890 N chromatograph, a capillary column DB-1 (60
m ꢃ 0.32 mm ꢃ 0.5 lm) packed with dimethylsiloxane. The
In summary, we have described the synthesis of novel
2,3-dihydro-3-hydroperoxy-2-aryl-4,5-diphenylisothia-
zole 1,1-dioxides by oxidation of the 2-aryl-4,5-diphenyl
substituted isothiazolium salts with H2O2. We have
shown that these hydroperoxy sultams can act as epoxi-
dation agent in the epoxidation reaction of cyclooctene
catalyzed by MoB.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
Synthesis of Novel 2,3-Dihydro-3-hydroperoxy-2-aryl-4,5-diphenylisothiazole
1,1-Dioxides and Their Epoxidation Ability
849
column temperature was changed from 50 up to 250ꢁC with
rate of 10ꢁ in 1 min.
[10] Gennari, C.; Nestlei, H. P.; Salon, B.; Still, W. C. Angew
Chem Int Ed Engl 1995, 34, 176.
[11] Gennari, C.; Salon, B.; Potenza, D.; Williams, A. Angew
Chem Int Ed Engl 1994, 33, 2067.
[12] Rogatchov, V. O.; Bernsmann, H.; Schwab, P.; Frohlich,
R.; Wibbeling, B.; Metza, P. Tetrahedron Lett 2002, 43, 4753.
[13] Wanner, J.; Harned, A. M.; Probst, D. A.; Poon, K. W.; Klein,
T. A.; Snelgrove, K. A.; Hanson, P. R. Tetrahedron Lett 2002, 43, 917.
[14] Alvarez-Ibarra, C.; Csaky, A. G.; Gomez de la Oliva, C.;
Rodriguez, E. Tetrahedron Lett 2001, 42, 2129.
Acknowledgments. The work was partly supported by the
Deutscher Akademischer Austauschdienst (DAAD) and by the
Graduiertenkolleg 378 ‘‘Mechanistische und Anwendungsas-
pekte nichtkonventioneller Oxidationsreaktionen.’’
[15] Lee, A. W. M.; Chan, W. H.; Yuen, W. H.; Xia, P. F.;
Wong, W. Y. Tetrahedron Asymmetry 1999, 10, 1421.
[16] Trentmann, W.; Mehler, T.; Martens, J. Tetrahedron Asym-
metry 1997, 8, 2033.
REFERENCES AND NOTES
[1] Bowman, W. C.; Ram, M. J. Textbook of Pharmacology,
2nd ed.; Blackwell: London, 1979; Chapter 34.
[17] Gelalcha, F. G.; Schulze, B. J Org Chem 2002, 67, 8400.
[18] Gelalcha, F. G. Chem Rev 2007, 107, 3338.
[19] Makota, O.; Wolf, J.; Trach, Yu.; Schulze, B. Appl Catal A
2007, 323, 174.
[2] Spaltenstein, A.; Almond, M. R.; Bock, W. J.; Cleary, D.
G.; Furfine, E. S.; Hazen, R. J.; Kazmierski, W. M.; Salituro, F. G.;
Tung, R. D.; Wright, L. R. Bioorg Med Chem Lett 2000, 11, 1159.
[3] Elghamry, I.; Dopp, D. Tetrahedron Lett 2001, 42, 5651.
[4] Wanner, J.; Harned, A. M.; Probst, D. A.; Poon, K. W.;
Klein, T. A.; Snelgrove, K. A.; Hanson, P. R. Tetrahedron Lett 2002,
43, 917.
[20] Schulze, B.; Obst, U.; Zahn, G.; Friedrich, B.; Cimiraglia,
R.; Hofmann, H.-J. J Prakt Chem/Chem Ztg 1995, 337, 17.
[21] Fahrig, J.; Freysoldt, T. H. E.; Hartung, C.; Sieler, J.;
Schulze, B. J Sulfur Chem 2005, 26, 211.
[5] Vree, T. B.; Hekstar, Y. A. Antibiol Chemother 1987, 37, 1.
[6] Enders, D.; Wallert, S. Tetrahedron Lett 2001, 42, 5651.
[7] Obniska, J.; Jurczyk, S.; Zeic, A.; Kaminski, K.; Tatarczyn-
ska, E.; Stachowicz, K. Pharm Rep 2005, 57, 170.
[22] Sheldon, R. A. J Mol Catal 1980, 7, 107.
[23] Sobczak, J. M.; Ziolkowski, J. J. Appl Catal A 2003, 248,
261.
[24] Trach, Yu.; Makota, O. Int J Chem Kinet 2009, 41, 623.
[25] Kokatnur, V. R.; Jelling, M. J Am Chem Soc 1941, 63,
1432.
[8] Davis, M. Adv Heterocycl Chem 1985, 38, 105.
[9] De, A. Prog Med Chem 1981, 18, 117.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet